The long-term objective of our research is to understand the mechanism of translation initiation in eukaryotes, its control under physiological conditions, and deregulation in diseases, such as cancer, diabetes and virus infection. Here, we propose to pursue our studies on the mechanism of function of the mRNA poly(A) binding protein (PABP) in translation initiation, and its regulation by members of a family of proteins known as PABP- interacting proteins (Paips), which were discovered in our laboratory. We demonstrated that Paip1 stimulates translation, whereas Paip2A and Paip2B inhibit translation. We propose three specific aims, which are as follows: 1. Investigate the function of a newly discovered complex, eIF3-Paip1. The molecular mechanism by which Paip1 stimulates translation will be studied, including a detailed structural characterization of the Paip1- eIF3 interaction. 2. Characterize the signaling pathways that regulate eIF3-Paip1 complex formation. We will determine whether phosphorylation of eIF3 regulates Paip1 binding and activity. Mutational analyses will be performed to study downstream effects of eIF3 phosphorylation on Paip1 function in translation. 3. Elucidate the physiological roles of Paip2A and Paip2B in animal models. Single knockout (KO) of Paip2A and Paip2B mice have recently been generated in our lab. Based on the known tissue distribution of the Paip2 proteins, we also intend to generate brain- and pancreas-specific KO mice. Mice will be subjected to complete phenotypic, pathological and histological examinations, and will be studied for effects on beta-cell regulation in the pancreas and on synaptic plasticity and memory formation in the brain. PUBLIC HEALTH RELEVANCE Many major diseases including cancer, diabetes and obesity arise because of defects in the control of the synthesis of proteins. We are studying an important example of such control, which involves a protein called poly(A) binding protein and its binding partners. Poly(A) binding protein binds to the tail of the genetic material (messenger RNA) that serves as template for the synthesis of all proteins in the cell.